tbuckley/cabot-search huggingface dataset:
Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)
Authors: Sophie Steinhäuser, Patricia Silva, Lennart Lenk, Thomas Beder, Alina Hartmann, Sonja Hänzelmann, Lars Fransecky, Martin Neumann, Lorenz Bastian, Simone Lipinski, Kathrin Richter, Miriam Bultmann, Emely Hübner, Shuli Xia, Christoph Röllig, Fotini Vogiatzi, Denis Martin Schewe, Veronica Yumiceba, Kristin Schultz, Malte Spielmann, Claudia Dorothea Baldus
Journal: Leukemia (2022)

Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation by CTCF-anchor methylation and upregulated oncogene expression in glioma, correlating with poor prognosis. Here, we investigated the role of IDH1 p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRA in IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRA in IDH1-mutant patients. Increased PDGFRA expression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1 p.R132H mutation and upon exogenous 2-HG treatment. IDH1-mutant cells showed higher sensitivity to tyrosine kinase inhibitor dasatinib, which was supported by reduced blast count in a patient with refractory IDH1-mutant AML after dasatinib treatment. Our data illustrate that IDH1 p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRA upregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML.
Fluid Bolus Administration and Cardiovascular Collapse in Critically Ill Patients Undergoing Tracheal Intubation
Authors: Ward H. van der Ven, Alexander P. J. Vlaar, Denise P. Veelo
Journal: JAMA (2022)

To the Editor The authors of the PREPARE II trial1 reported no significant effect of a fluid bolus before tracheal intubation on the incidence of cardiovascular collapse shortly after this procedure. We have several concerns about this study.
Bias in Assessment Needs Urgent Attention—No Rest for the “Wicked”
Authors: Vineet M. Arora, Keme Carter, Christine Babcock
Journal: JAMA Network Open (2022)

Mira Mamtani, MD, MSEd; Frances Shofer, PhD; Kevin Scott, MD, MSEd; Dana Kaminstein, PhD; Whitney Eriksen, PhD, WHNP; Michael Takacs, MD; Andrew K. Hall, MD; Anna Weiss, MD, MSEd; Lauren A. Walter, MD; Fiona Gallahue, MD; Lainie Yarris, MD, MCR; Stephanie B. Abbuhl, MD; Jaya Aysola, MD, DTMH, MPH
Fluid Bolus Administration and Cardiovascular Collapse in Critically Ill Patients Undergoing Tracheal Intubation—Reply
Authors: Derek W. Russell, Jonathan D. Casey, Matthew W. Semler
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Correspondence on Letter regarding “The usefulness of metabolic score for insulin resistance for the prediction of incident non-alcoholic fatty liver disease in Korean adults”
Authors: Jun-Hyuk Lee, Kyongmin Park, Hye Sun Lee, Hoon-Ki Park, Jee Hye Han, Sang Bong Ahn
Journal: Clinical and Molecular Hepatology (2022)

Keywords: Insulin resistance; Metabolic score for insulin resistance; Homeostatic model assessment for insulin resistance; Non-alcoholic fatty liver disease; Fatty liver
Understanding and neutralising covid-19 misinformation and disinformation
Authors: Yuxi Wang, John Bye, Karam Bales, Deepti Gurdasani, Adityavarman Mehta, Mohammed Abba-Aji, David Stuckler, Martin McKee,
Journal: BMJ (2022)

<b>Yuxi Wang and colleagues</b> say that the public inquiry on covid-19 must look at who was opposing public health measures and why and should call on public health authorities to engage more effectively with the threats of infodemics
Pathophysiology and pharmacology of G protein-coupled receptors in the heart
Authors: Alyssa Grogan, Emilio Y Lucero, Haoran Jiang, Howard A Rockman
Journal: Cardiovascular Research (2022)

Abstract G protein-coupled receptors (GPCRs), comprising the largest superfamily of cell surface receptors, serve as fundamental modulators of cardiac health and disease owing to their key roles in the regulation of heart rate, contractile dynamics, and cardiac function. Accordingly, GPCRs are heavily pursued as drug targets for a wide variety of cardiovascular diseases ranging from heart failure, cardiomyopathy, and arrhythmia to hypertension and coronary artery disease. Recent advancements in understanding the signalling mechanisms, regulation, and pharmacological properties of GPCRs have provided valuable insights that will guide the development of novel therapeutics. Herein, we review the cellular signalling mechanisms, pathophysiological roles, and pharmacological developments of the major GPCRs in the heart, highlighting the β-adrenergic, muscarinic, and angiotensin receptors as exemplar subfamilies.
Changing patterns in reporting and sharing of review data in systematic reviews with meta-analysis of the effects of interventions: cross sectional meta-research study
Authors: Phi-Yen Nguyen, Raju Kanukula, Joanne E McKenzie, Zainab Alqaidoom, Sue E Brennan, Neal R Haddaway, Daniel G Hamilton, Sathya Karunananthan, Steve McDonald, David Moher, Shinichi Nakagawa, David Nunan, Peter Tugwell, Vivian A Welch, Matthew J Page
Journal: BMJ (2022)

To examine changes in completeness of reporting and frequency of sharing data, analytical code, and other review materials in systematic reviews over time; and factors associated with these changes.Cross sectional meta-research study.Random sample of 300 systematic reviews with meta-analysis of aggregate data on the effects of a health, social, behavioural, or educational intervention. Reviews were indexed in PubMed, Science Citation Index, Social Sciences Citation Index, Scopus, and Education Collection in November 2020.The extent of complete reporting and the frequency of sharing review materials in the systematic reviews indexed in 2020 were compared with 110 systematic reviews indexed in February 2014. Associations between completeness of reporting and various factors (eg, self-reported use of reporting guidelines, journal policies on data sharing) were examined by calculating risk ratios and 95% confidence intervals.Several items were reported suboptimally among 300 systematic reviews from 2020, such as a registration record for the review (n=113; 38%), a full search strategy for at least one database (n=214; 71%), methods used to assess risk of bias (n=185; 62%), methods used to prepare data for meta-analysis (n=101; 34%), and source of funding for the review (n=215; 72%). Only a few items not already reported at a high frequency in 2014 were reported more frequently in 2020. No evidence indicated that reviews using a reporting guideline were more completely reported than reviews not using a guideline. Reviews published in 2020 in journals that mandated either data sharing or inclusion of data availability statements were more likely to share their review materials (eg, data, code files) than reviews in journals without such mandates (16/87 (18%) v 4/213 (2%)).Incomplete reporting of several recommended items for systematic reviews persists, even in reviews that claim to have followed a reporting guideline. Journal policies on data sharing might encourage sharing of review materials.
RP2-Associated X-linked Retinopathy
Authors: Michalis Georgiou, Anthony G. Robson, Katarina Jovanovic, Thales A. C. de Guimarães, Naser Ali, Nikolas Pontikos, Sami H. Uwaydat, Omar A. Mahroo, Michael E. Cheetham, Andrew R. Webster, Alison J. Hardcastle, Michel Michaelides
Journal: Ophthalmology (2022)
Opposite evolution of pathogenicity driven by in vivo wzc and wcaJ mutations in ST11-KL64 carbapenem-resistant Klebsiella pneumoniae
Authors: Jintao He, Qiucheng Shi, Zhifu Chen, Wang Zhang, Peng Lan, Qingye Xu, Huangdu Hu, Qiong Chen, Jianzhong Fan, Yan Jiang, Belinda Loh, Sebastian Leptihn, Quanming Zou, Jinyong Zhang, Yunsong Yu, Xiaoting Hua
Journal: Drug Resistance Updates (2022)
Enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2
Authors: Panke Qu, John P. Evans, Julia N. Faraone, Yi-Min Zheng, Claire Carlin, Mirela Anghelina, Patrick Stevens, Soledad Fernandez, Daniel Jones, Gerard Lozanski, Ashish Panchal, Linda J. Saif, Eugene M. Oltz, Kai Xu, Richard J. Gumina, Shan-Lu Liu
Journal: Cell Host & Microbe (2022)
Disrupting circadian control of peripheral myogenic reactivity mitigates cardiac injury following myocardial infarction
Authors: Jeffrey T Kroetsch, Darcy Lidington, Faisal J Alibhai, Cristine J Reitz, Hangjun Zhang, Danny D Dinh, Julia Hanchard, Tarak N Khatua, Scott P Heximer, Tami A Martino, Steffen-Sebastian Bolz
Journal: Cardiovascular Research (2022)

Abstract Aims Circadian rhythms orchestrate important functions in the cardiovascular system: the contribution of microvascular rhythms to cardiovascular disease progression/severity is unknown. This study hypothesized that (i) myogenic reactivity in skeletal muscle resistance arteries is rhythmic and (ii) disrupting this rhythmicity would alter cardiac injury post-myocardial infarction (MI). Methods and results Cremaster skeletal muscle resistance arteries were isolated and assessed using standard pressure myography. Circadian rhythmicity was globally disrupted with the ClockΔ19/Δ19 mutation or discretely through smooth muscle cell-specific Bmal1 deletion (Sm-Bmal1 KO). Cardiac structure and function were determined by echocardiographic, hemodynamic and histological assessments. Myogenic reactivity in cremaster muscle resistance arteries is rhythmic. This rhythm is putatively mediated by the circadian modulation of a mechanosensitive signalosome incorporating tumour necrosis factor and casein kinase 1. Following left anterior descending coronary artery ligation, myogenic responsiveness is locked at the circadian maximum, although circadian molecular clock gene expression cycles normally. Disrupting the molecular clock abolishes myogenic rhythmicity: myogenic tone is suspended at the circadian minimum and is no longer augmented by MI. The reduced myogenic tone in ClockΔ19/Δ19 mice and Sm-Bmal1 KO mice associates with reduced total peripheral resistance (TPR), improved cardiac function and reduced infarct expansion post-MI. Conclusions Augmented microvascular constriction aggravates cardiac injury post-MI. Following MI, skeletal muscle resistance artery myogenic reactivity increases specifically within the rest phase, when TPR would normally decline. Disrupting the circadian clock interrupts the MI-induced augmentation in myogenic reactivity: therapeutics targeting the molecular clock, therefore, may be useful for improving MI outcomes.
Atypical enteropathogenic <i>E. coli</i> are associated with disease activity in ulcerative colitis
Authors: Maximilian Baumgartner, Rebecca Zirnbauer, Sabine Schlager, Daniel Mertens, Nikolaus Gasche, Barbara Sladek, Craig Herbold, Olga Bochkareva, Vera Emelianenko, Harald Vogelsang, Michaela Lang, Anton Klotz, Birgit Moik, Athanasios Makristathis, David Berry, Stefanie Dabsch, Vineeta Khare, Christoph Gasche
Journal: Gut Microbes (2022)

With increasing urbanization and industrialization, the prevalence of inflammatory bowel diseases (IBDs) has steadily been rising over the past two decades. IBD involves flares of gastrointestinal (GI) inflammation accompanied by microbiota perturbations. However, microbial mechanisms that trigger such flares remain elusive. Here, we analyzed the association of the emerging pathogen atypical enteropathogenic E. coli (aEPEC) with IBD disease activity. The presence of diarrheagenic E. coli was assessed in stool samples from 630 IBD patients and 234 age- and sex-matched controls without GI symptoms. Microbiota was analyzed with 16S ribosomal RNA gene amplicon sequencing, and 57 clinical aEPEC isolates were subjected to whole-genome sequencing and in vitro pathogenicity experiments including biofilm formation, epithelial barrier function and the ability to induce pro-inflammatory signaling. The presence of aEPEC correlated with laboratory, clinical and endoscopic disease activity in ulcerative colitis (UC), as well as microbiota dysbiosis. In vitro, aEPEC strains induce epithelial p21-activated kinases, disrupt the epithelial barrier and display potent biofilm formation. The effector proteins espV and espG2 distinguish aEPEC cultured from UC and Crohn's disease patients, respectively. EspV-positive aEPEC harbor more virulence factors and have a higher pro-inflammatory potential, which is counteracted by 5-ASA. aEPEC may tip a fragile immune–microbiota homeostasis and thereby contribute to flares in UC. aEPEC isolates from UC patients display properties to disrupt the epithelial barrier and to induce pro-inflammatory signaling in vitro.
Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylase 1 and 2
Authors: Paulina X. Medina Rangel, Elizabeth Cross, Chang Liu, Christopher E. Pedigo, Xuefei Tian, Elena Gutiérrez-Calabrés, Soichiro Nagata, Anupama Priyadarshini, Gabriel Lerner, Patricia Bunda, Sudhir Perincheri, Jianlei Gu, Hongyu Zhao, Ying Wang, Kazunori Inoue, Shuta Ishibe
Journal: Journal of the American Society of Nephrology (2022)

Background Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence. Methods Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development. Results Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine. Conclusions Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.
Values in challenging times: strategic crisis management in the EU
Authors: Barbara Prainsack, Maria do Céu Patrão Neves, Nils-Eric Sahlin, Nikola Biller-Andorno, Migle Laukyte, Paweł Łuków, Herman Nys, Jeroen van den Hoven, Pierre Mallia, Fruzsina Molnár-Gábor, Thérèse Murphy, Laura Palazzani, Tamar Sharon, Renata Veselska, Takis Vidalis
Journal: The Lancet Regional Health - Europe (2022)
Hemophilia “A” gene therapy: Lost in translation
Authors: Thierry VandenDriessche, Marinee K Chuah
Journal: Molecular Therapy (2022)

Successful gene therapy for hemophilia A had been considered as one of the “holy grails” in the gene therapy field. An important milestone toward realizing this goal had been achieved (https://www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia) following the first conditional marketing authorization approval in the European Union for an adeno-associated virus type 5 (AAV5)-based gene therapy strategy.1 Most of the treated patients remained off prophylaxis and bleed-free 2 years after dosing and up to 5 years in a supporting trial.
TEMPO enables sequential genetic labeling and manipulation of vertebrate cell lineages
Authors: Isabel Espinosa-Medina, Daniel Feliciano, Carla Belmonte-Mateos, Rosa Linda Miyares, Jorge Garcia-Marques, Benjamin Foster, Sarah Lindo, Cristina Pujades, Minoru Koyama, Tzumin Lee
Journal: Neuron (2022)

During development, regulatory factors appear in a precise order to determine cell fates over time. Consequently, to investigate complex tissue development, it is necessary to visualize and manipulate cell lineages with temporal control. Current strategies for tracing vertebrate cell lineages lack genetic access to sequentially produced cells. Here, we present TEMPO (Temporal Encoding and Manipulation in a Predefined Order), an imaging-readable genetic tool allowing differential labeling and manipulation of consecutive cell generations in vertebrates. TEMPO is based on CRISPR and powered by a cascade of gRNAs that drive orderly activation and inactivation of reporters and/or effectors. Using TEMPO to visualize zebrafish and mouse neurogenesis, we recapitulated birth-order-dependent neuronal fates. Temporally manipulating cell-cycle regulators in mouse cortex progenitors altered the proportion and distribution of neurons and glia, revealing the effects of temporal gene perturbation on serial cell fates. Thus, TEMPO enables sequential manipulation of molecular factors, crucial to study cell-type specification.
Effectiveness of Bivalent mRNA Vaccines in Preventing Symptomatic SARS-CoV-2 Infection — Increasing Community Access to Testing Program, United States, September–November 2022
Authors: Ruth Link-Gelles, Allison Avrich Ciesla, Katherine E. Fleming-Dutra, Zachary R. Smith, Amadea Britton, Ryan E. Wiegand, Joseph D. Miller, Emma K. Accorsi, Stephanie J. Schrag, Jennifer R. Verani, Nong Shang, Gordana Derado, Tamara Pilishvili
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

On September 1, 2022, bivalent COVID-19 mRNA vaccines, composed of components from the SARS-CoV-2 ancestral and Omicron BA.4/BA.5 strains, were recommended by the Advisory Committee on Immunization Practices (ACIP) to address reduced effectiveness of COVID-19 monovalent vaccines during SARS-CoV-2 Omicron variant predominance (1). Initial recommendations included persons aged ≥12 years (Pfizer-BioNTech) and ≥18 years (Moderna) who had completed at least a primary series of any Food and Drug Administration-authorized or -approved monovalent vaccine ≥2 months earlier (1). On October 12, 2022, the recommendation was expanded to include children aged 5-11 years. At the time of recommendation, immunogenicity data were available from clinical trials of bivalent vaccines composed of ancestral and Omicron BA.1 strains; however, no clinical efficacy data were available. In this study, effectiveness of the bivalent (Omicron BA.4/BA.5-containing) booster formulation against symptomatic SARS-CoV-2 infection was examined using data from the Increasing Community Access to Testing (ICATT) national SARS-CoV-2 testing program.* During September 14-November 11, 2022, a total of 360,626 nucleic acid amplification tests (NAATs) performed at 9,995 retail pharmacies for adults aged ≥18 years, who reported symptoms consistent with COVID-19 at the time of testing and no immunocompromising conditions, were included in the analysis. Relative vaccine effectiveness (rVE) of a bivalent booster dose compared with that of ≥2 monovalent vaccine doses among persons for whom 2-3 months and ≥8 months had elapsed since last monovalent dose was 30% and 56% among persons aged 18-49 years, 31% and 48% among persons aged 50-64 years, and 28% and 43% among persons aged ≥65 years, respectively. Bivalent mRNA booster doses provide additional protection against symptomatic SARS-CoV-2 in immunocompetent persons who previously received monovalent vaccine only, with relative benefits increasing with time since receipt of the most recent monovalent vaccine dose. Staying up to date with COVID-19 vaccination, including getting a bivalent booster dose when eligible, is critical to maximizing protection against COVID-19 (1).
Paxlovid Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022
Authors: Melisa M. Shah, Brendan Joyce, Ian D. Plumb, Sam Sahakian, Leora R. Feldstein, Eric Barkley, Mason Paccione, Joseph Deckert, Danessa Sandmann, Jacqueline L. Gerhart, Melissa Briggs Hagen
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Nirmatrelvir-ritonavir (Paxlovid), an oral antiviral treatment, is authorized for adults with mild-to-moderate COVID-19 who are at increased risk for progression to severe illness. However, real-world evidence on the benefit of Paxlovid, according to vaccination status, age group, and underlying health conditions, is limited. To examine the benefit of Paxlovid in adults aged ≥18 years in the United States, a large electronic health record (EHR) data set (Cosmos†) was analyzed to assess the association between receiving a prescription for Paxlovid and hospitalization with a COVID-19 diagnosis in the ensuing 30 days. A Cox proportional hazards model was used to estimate this association, adjusted for demographic characteristics, geographic location, vaccination, previous infection, and number of underlying health conditions. Among 699,848 adults aged ≥18 years eligible for Paxlovid during April-August 2022, 28.4% received a Paxlovid prescription within 5 days of COVID-19 diagnosis. Being prescribed Paxlovid was associated with a lower hospitalization rate among the overall study population (adjusted hazard ratio [aHR] = 0.49), among those who had received ≥3 mRNA COVID-19 vaccines (aHR = 0.50), and across age groups (18-49 years: aHR = 0.59; 50-64 years: aHR = 0.40; and ≥65 years: aHR = 0.53). Paxlovid should be prescribed to eligible adults to reduce the risk of COVID-19-associated hospitalization.